EP3072882A1 - Substituierte methylamine, serotonin-5-ht6-rezeptorantagonisten, verfahren zur herstellung und verwendung davon - Google Patents

Substituierte methylamine, serotonin-5-ht6-rezeptorantagonisten, verfahren zur herstellung und verwendung davon Download PDF

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EP3072882A1
EP3072882A1 EP16000808.2A EP16000808A EP3072882A1 EP 3072882 A1 EP3072882 A1 EP 3072882A1 EP 16000808 A EP16000808 A EP 16000808A EP 3072882 A1 EP3072882 A1 EP 3072882A1
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methyl
amine
piperazin
methylpiperazin
chlorophenylsulfonyl
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Alexandre Vasilievich IVACHTCHENKO
Oleg Dmitrievich Mitkin
Madina Georgievna Kadieva
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Alla Chem LLC
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Definitions

  • the invention relates to novel substituted methyl-amines, to novel serotonin 5-HT 6 receptor antagonists, to novel active components, pharmaceutical compositions, therapeutic kits, method for treatment and molecular instruments.
  • novel active components In the origin of pharmacological effect of novel active components is their ability to interact with serotonin 5-HT 6 receptors playing a key role in treatment of central nervous system (CNS) diseases, in particular, Alzheimer's disease (AD), Huntington's disease, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.
  • CNS central nervous system
  • 5-HT 6 receptors are modulators of the whole number of neuromediator systems including cholinergic, noradrenergic, glutamatergic and dopaminergic. Taking into account the fundamental role of these systems in normal cognitive processes and their dysfunction at neurodegeneration, exclusive role of 5-HT 6 receptors in forming normal and "pathological" memory becomes obvious.
  • 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation an effect sensitive to NMDA receptor antagonism.
  • Neuropharmacology 2004; 47:195-204 It was also demonstrated that considerable enhancement of cognitive functions in aged rats in Morrison's water maze experiment took place under the action of 5-HT 6 receptor antagonists [ Foley A.G., Murphy K.J., Hirst W.D., Gallagher H.C., Hagan J.J., Upton N., Walsh F.S., Regan C.M.
  • the 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.
  • 5-HT 6 receptor antagonists are at various phases of clinical trials as potential ingredients for treatment of AD, Huntington's disease, schizophrenia (antipsychotic) and other neurodegenerative and cognitive diseases (Table 1) [http://integrity.prous.com].
  • Table 1 5-HT 6 Receptor antagonists as drug candidates.
  • Medicament Clinical phase of testing Developer Therapeutic group Dimebon TM Phase III Medivation (USA) Alzheimer's disease treatment SGS-518 Phase II Lilly, Saegis Cognitive diseases treatment SB-742457 Phase II GlaxoSmithKline Alzheimer's disease treatment; Antipsychotic Dimebon* Phase I/IIa Medivation (USA) Huntington's disease treatment Dimebon* Phase II (Russia) Schizophrenia PRX-07034 Phase I Epix Pharm.
  • 5-HT 6 receptor antagonists Another attractive property of 5-HT 6 receptor antagonists is their ability to suppress appetite that can lead to the development of essentially novel remedies for lowering of overweight and obesity on their basis.
  • Vicker S.P. Dourish C.T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388 ].
  • This effect was confirmed in many investigations [ Holenz J., Pauwels P.J., Diaz J.L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299 . Davies S.L.
  • the purpose of the present invention is novel substituted methyl-amines exhibiting activity towards 5-HT 6 receptors.
  • the preferable methyl-amines are compounds 1.1 - 1.8, where W represents optionally substituted 1,2-phenylene (1.1 ); 1,2-naphthalinene (1.2.1, 1.2.2, 1.3); 1,2-indolizinene (1.4.1, 1.4.2); 3,4-quinolinene (1.5 1.7), 5,6-quinolinene (1.6) or 4,5-oxazolene (1.8), wherein:
  • the preferable methyl-amines are also compounds of the general formulas 1.1-1.8, where R2 represents hydrogen, methyl, piperazin-1-yl or 4-methylpiperazin-1-yl.
  • the more preferable methyl-amines of the general formula 1.1 are compounds selected from the group consisting of: methyl-[3-(piperazin-1-yl-6-(3-chlorophenylsulfonyl)phenyl]-amine 1.1 (2), methyl-[3-(4-methyl-piperazin-1-yl)-6-(3-chlorophenylsulfonyl)phenyl]-amine 1.1(5), methyl-(4-piperazin-1-yl-6-phenylsulfonylphenyl)-amine 1.1(7), methyl-[4-piperazin-1-yl-6-(3-chlorophenylsulfonyl)phenyl]-amine 1.1(8), methyl-[4-piperazin-1-yl-6-(3-fluorophenylsulfonyl)phenyl]-amine 1.1 (9), methyl-[4-(4-methylpiperazin-1-yl)-6-phenyls
  • the more preferable methyl-amines of the general formulas 1.2.1 and 1.2.2 are the compounds selected from the group consisting of: methyl-(4-piperazin-1-yl-2-phenylsulfonylnaphthalen-1-yl)-amine 1.2.1 (1), methyl-[4-piperazin-1-yl-2-(3-chlorophenylsulfonyl)naphthalen-1-yl]-amine 1.2.1 (2), methyl-[4-piperazin-1-yl-2-(3-fluorophenylsulfonyl)naphthalen-1-yl]-amine 1.2.1(3), methyl-[4-(4-methylpiperazin-1-yl)-2-phenylsulfonylnaphthalen-1-yl)-amine 1.2.1(4), methyl-[4-(4-methylpiperazin-1-yl)-2-(3-chlorophenylsulfonyl)naphthalen-1-yl]-amine 1.2.1
  • the more preferable methyl-amines of the general formula 1.3 are the compounds selected from the group consisting of: methyl-(4-piperazin-1-yl-1-phenylsulfonylnaphthalen-2-yl)-amine 1.3(1), methyl-[4-piperazin-1-yl-1-(1-chlorophenylsulfonyl)naphthalen-2-yl]-amine 1.3(2), methyl-[4-piperazin-1-yl-1-(1-fluorophenylsulfonyl)naphthalen-2-yl]-amine 1.3(3), methyl-[4-(4-methylpiperazin-1-yl)-1-phenylsulfonylnaphthalen-2-yl]-amine 1.3(4), methyl-[4-(4-methylpiperazin-1-yl)-1-(3-chlorophenylsulfonyl)naphthalen-2-yl]-amine 1.3(5), methyl
  • methyl-amines of the general formulas 1.4.1 and 1.4.2 are the compounds selected from the group consisting of: methyl-(1-phenylsulfonylindolizin-2-yl)-amine 1.4.1 (1), methyl-[1-(3-chlorophenylsulfonyl)indolizin-2-yl]-amine 1.4.1(2), methyl-[1-(3-fluorophenylsulfonyl)indolizin-2-yl]-amine 1.4.1 (3), methyl-(3-methyl-1-phenylsulfonylindolizin-2-yl)-amine 1.4.1 (4), methyl-[3-methyl-1-(3-chlorophenylsulfonyl)indolizin-2-yl]-amine 1.4.1(5), methyl-[3-methyl-1-(3-fluorophenylsulfonyl)indolizin-2-yl]-amine 1.4.1(6), methyl-(3-piperazin-1-
  • methyl-amines of the general formulas 1.5 are the compounds selected from the group consisting of: methyl-(8-piperazin-1-yl-3-phenylsulfonylquinolin-4-yl)-amine 1.5(1), methyl-[8-piperazin-1-yl-3-(3-chlorophenylsulfonyl)quinolin-4-yl]-amine 1.5(2), methyl-[8-piperazin-1-yl-3-(3-fluorophenylsulfonyl)quinolin-4-yl]-amine 1.5(3), methyl-[8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinolin-4-yl]-amine 1.5(4), methyl-[8-(4-methylpiperazin-1-yl)-3-(3-chlorophenylsulfonyl)quinolin-4-yl]-amine 1.5(5), methyl-[8-(4-methylpiperazin-1-y
  • the more preferable methyl-amines of the general formulas 1.6 are the compounds selected from the group consisting of: methyl-(8-piperazin-1-yl-5-phenylsulfonylquinolin-6-yl)-amine 1.6(1), methyl-[8-piperazin-1-yl-5-(3-chlorophenylsulfonyl)quinolin-6-yl]-amine 1.6(2), methyl-[8-piperazin-1-yl-5-(3-fluorophenylsulfonyl)quinolin-6-yl]-amine 1.6(3), methyl-[8-(4-methylpiperazin-1-yl)-5-phenylsulfonylquinolin-6-yl]-amine 1.6(4), methyl-[8-(4-methylpiperazin-1-yl)-5-(3-chlorophenylsulfonyl)quinolin-6-yl]-amine 1.6(5), methyl-[8-
  • the more preferable methyl-amines of the general formulas 1.7 are the compounds selected from the group consisting of: methyl-(8-piperazin-1-yl-4-phenylsulfonylquinolin-3-yl)-amine 1.7(1), methyl-[8-piperazin-1-yl-4-(3-chlorophenylsulfonyl)quinolin-3-yl]-amine 1.7(2), methyl-[8-piperazin-1-yl-4-(3-fluorophenylsulfonyl)quinolin-3-yl]-amine 1.7(3), methyl-[8-(4-methylpiperazin-1-yl)-4-phenylsulfonylquinolin-3-yl]-amine 1.7(4), methyl-[8-(4-methylpiperazin-1-yl)-4-(3-chlorophenylsulfonyl)quinolin-3-yl]-amine 1.7(5), methyl-[8-
  • methyl-amines of the general formulas 1.8 are the compounds selected from the group consisting of: methyl-[2-methyl-4-(3-chlorophehylsulfonyl)oxazol-5-yl]-amine 1.8(2), methyl-[2-methyl-4-(3-fluorophenylsulfonyl)oxazol-5-yl]-amine 1.8(3), methyl-(2-piperazin-1-yl-4-phenylsulfonyloxazol-5-yl)-amine 1.8(4), methyl-[2-piperazin-1-yl-4-(3-chlorophenylsulfonyl)oxazol-5-yl]-amine 1.8(5), methyl-[2-piperazin-1-yl-4-(3-fluorophenylsulfonyl)oxazol-5-yl]-amine 1.8(6), methyl-[2-(4-methylpiperazin-1-yl)-4-phenyls
  • Substituted methyl-amines of the general formula 1 were prepared using well-known reactions. If as a result of the reaction one product was formed predominantly, it was isolated from the reaction mixture and subjected to purification by known methods, for example, recrystallization or chromatography. If there was a mixture of two compounds it was separated, for example, by means of preparative chromatography.
  • Methyl-(3-piperazin-1-yl-6-phenylsulfonylphenyl)-amine 1.1(2) was prepared starting from 2-nitro-1,4-difluorobenzene 2 (1) according to the scheme given below.
  • Methyl-(4-phenylsulfonyl-biphenyl-3-yl)-amine 1.1 (13) was prepared starting from 2-nitro-4-iodo-chlorobenzene 4 (1) according to scheme 2 given below.
  • Methyl-(5-pyridin-3-yl-2-phenylsulfonylphenyl)-amine 1.1(14) was prepared starting from 3-nitro-4-phenylsulfonyl-iodobebzene 4 (3) according to scheme 3 given below.
  • Methyl-(1-phenylsulfonylindolizin-2-yl)-amine 1.4.1 (1) was prepared starting from 2-(chloromethyl)pyridine 6 (1) according to scheme 7 given below. wherein
  • Methyl-(3-methyl-1-phenylsulfonylindolizin-2-yl)-amine 1.4.1(4) was prepared starting from compound 6 (6) according to scheme 8 given below.
  • Methyl-(8-piperazin-1-yl-3-phenylsulfonylquinolin-4-yl)-amine 1.5(1) and methyl-(3-phenylsulfonyl-8-fluoroquinolin-4-yl)-amine 1.5(8) were prepared starting from 3-fluoro-aniline 7 (1) according to scheme 10.
  • Methyl-(3-phenylsulfonylquinolin-4-yl)-amine 1.5(7) was prepared starting from aniline 8 (1) according to scheme 11 given below.
  • the subject of the present invention is serotonin 5-HT 6 receptor antagonists representing substituted methyl-amines of the general formula 1, conceivably also in crystalline form or in the form of pharmaceutically acceptable salts.
  • the subject of the present invention is an active component for pharmaceutical compositions and medicaments representing at least one substituted methyl-amine of the general formula 1, conceivably in crystalline form or in the form of pharmaceutically acceptable salts exhibiting properties of serotonin 5-HT 6 receptor antagonist.
  • the subject of the present invention is also a pharmaceutical composition for prophylaxis and treatment of CNS diseases pathogenesis of which is associated with 5-HT 6 receptors including cognitive disorders and neurodegenerative diseases comprising an active component representing at least one substituted methyl-amine of the general formula 1, conceivably in crystalline form or in the form of pharmaceutically acceptable salts in pharmaceutically effective amount.
  • composition mentioned above in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.
  • compositions for prophylaxis and treatment of psychic disorders schizophrenia, anxiety disorders, enhancement of mental capacities, and also for prophylaxis and treatment of obesity.
  • the pharmaceutical composition may include pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients mean diluents, auxiliary agents and/or carriers applied in the sphere of pharmaceutics.
  • pharmaceutical composition together with an active component of the general formula 1 may include other active ingredients provided that they do not give rise to undesirable effects, such as allergic reactions.
  • compositions could be used in clinical practice in various forms prepared by mixing the said compositions with traditional pharmaceutical carries, for example, peroral forms (such as, tablets, gelatinous capsules, pills, solutions or suspensions); forms for injections (such as, solutions or suspensions for injections, or a dry powder for injections which requires only addition of water for injections before utilization); local forms (such as, ointments or solutions).
  • peroral forms such as, tablets, gelatinous capsules, pills, solutions or suspensions
  • forms for injections such as, solutions or suspensions for injections, or a dry powder for injections which requires only addition of water for injections before utilization
  • local forms such as, ointments or solutions.
  • the carriers used in pharmaceutical compositions represent carriers which are used in the sphere of pharmaceutics for preparation of commonly used forms. Binding agents, greasing agents, disintegrators, solvents, diluents, stabilizers, suspending agents, colorless agents, taste flavors are used for peroral forms; antiseptic agents, solubilizers, stabilizers are used in forms for injections; base materials, diluents, greasing agents, antiseptic agents are used in local forms.
  • the subject of the present invention is also a method for prophylaxis and treatment of CNS diseases pathogenesis of which is associated with 5-HT 6 receptors consisting in administration of active component or pharmaceutical composition mentioned above.
  • the pharmaceutical composition or active component could be introduced perorally or parenterally, for example, intravenous, subcutaneous, intraperitoneally or locally.
  • Clinical dose of active component or pharmaceutical composition may be corrected depending on: therapeutic efficiency and bio-accessibility of active ingredients in patients' organism, rate of their exchange and removal from organism, and age, gender, and severity of patient's symptoms.
  • the daily intake for adults normally being 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg.
  • each dose unit should contain 10 ⁇ 500 mg of an active component of the general formula 1, preferably 50 ⁇ 300 mg. Following the instructions of physician or pharmacist, these preparations could be taken several times over specified periods of time (preferably, from one to six times).
  • the subject of the present invention is also "molecular tools" for investigation of peculiarities of physiologically active compounds exhibiting the property to inhibit serotonin 5-HT 6 receptors, representing substituted methyl-amines of the general formula 1, conceivably also in crystalline form or in the form of pharmaceutically acceptable salts.
  • Reaction product 2(7) was isolated by means of HPLC method, it was dissolved in a small amount of methanol, equivalent amount of 0.2 M HCl solution in methanol was added, and the reaction product 1.1(2)-HCl was precipitated by ether and filtered off. Yield is 97%.
  • Argon was passed through a mixture of phenylboronic acid (186.5 mg, 1.52 mmol) and Na 2 CO 3 (406.8 mg, 3.83 mmol) in water ethanol (water 3.8 ml, ethanol 13.7 ml) at stirring for 30 min at 90°C, then cooled to 80°C and compound 4(3) (732.2 mg, 1.89 mmol) was added to the reaction mixture in argon current, inert gas was passed for another 10 min, then bis-triphenylphosphinepalladium dichloride (33.9 mg) was added and argon was passed for another 5 min. The reaction mixture was stirred for 2 h at 85°C in argon atmosphere, cooled, gradually formed solid was filtered off.
  • Argon was passed through a mixture of 3-pyridineboronic acid (187 mg, 1.53 mmol) and Na 2 CO 3 (408 mg, 3.84 mmol) in water ethanol (water 3.74 ml, ethanol 14.96 ml) at stirring at 90°C for 30 min and cooled to 80°C.
  • 4-lodo-2-nitro-1-(phenylsulfonyl)-benzene 4(3) (734 mg, 1.9 mmol) was added to the reaction mixture in argon current, inert gas was passed for another 10 min, then bis-triphenylphosphinepalladium dichloride (34 mg) was added and argon was passed for additional 5 min.
  • reaction mixture was stirred for 2 h at 85°C in argon atmosphere, then, cooled, water was added, and precipitated solid was filtered off.
  • the reaction product was extracted from mother liquor with CH 2 Cl 2 , organic layer was dried over Na 2 SO 4 , filtered and evaporated to dryness. The residue was suspended in CH 2 Cl 2 , filtered off, mother liquor was evaporated, the residue washed with diethyl ether, it gave 460 mg (70.5%) of 3-(3-nitro-4-(phenylsulfonyl)phenyl)pyridine 5(1).
  • Di- iso -butyl-aluminum hydride (1.1 ml, 1.7 mmol, 1.5 M) was added to a mixture of compound 5(3) (252 mg, 0.75 mmol) in dry toluene (2 ml). The mixture was stirred for 24 h at 20°C. It was washed with saturated NaHCO 3 solution, extracted with CH 2 Cl 2 , dried over Na 2 SO 4 , filtered and evaporated to dryness. The reaction product - N-methyl-2-(phenylsulfonyl)-5-(pyridin-3-yl)phenylamine 1.1(14) - was isolated by means of HPLC method.
  • Example 4 The general method for synthesis of substituted methyl-(4-piperazin-1-yl-2-phenylsulfonylnaphthalen-1-yl)-amines 1.2.1(1)-1.2.1(3). Scheme 4.
  • reaction product - compound 10 (6) was isolated by means of HPLC, the base was dissolved in a small amount of methanol, then equivalent amount of 0.2 M HCl solution in methanol was added. Reaction product 1.2.1(1) . HCl was precipitated with ether and filtered off. Yield was 97%.
  • N-(2-Bromo-5-nitronaphthalen-1-yl)acetamide 11 (1) (8.2 g, 30.7 mmol) was added to a suspension of 60% NaH (1.6 mg, 40 mmol) in DMF (30 ml) and mixture was stirred for 1 h at 50 0 C. The reaction mixture was cooled to room temperature, then methyl iodide (5 ml) was added. The mixture was stirred at room temperature for 15 h. The reaction solution was poured onto icy water and extracted with ethyl acetate. Organic layer was washed with salted water and evaporated at reduced pressure. The obtained residue was purified by column chromatography on silica, eluent hexane/ethyl acetate, from 4:1 to 3:2, it gave compound 11 (2), 9.9 g, (96%).
  • N-Boc-Aminoindazole 6(6) (0.74 g, 0.002 mol) was added to a suspension of lithium aluminum hydride (0.38 g, 0.01 mol) in absolute THF (50 ml) using external cooling with water. After the addition was completed the cooling was taken away, the reaction mixture was refluxed for 12 h, cooled, decomposed with water, stirred for 1 h; inorganic solid was filtered off; solvent was removed in vacuo; the residue was purified chromatographically (eluent - benzene-ethyl acetate, 25:1). It gave 0.26 g (45%) of methyl-1-(phenylsulfonylindolizin-2-yl)-amine 1.4.1(1).
  • Triethylamine (1.12 ml, 8.1 mmol) and Boc 2 O (1.47 g, 6.7 mmol) one after another were added to a solution of ethyl 1-(phenylsulfonyl)-3-(piperazin-1-yl)indolizine-2-carboxylate 6 (9) (2.77 g, 6.7 mmol) in CH 2 Cl 2 (20 ml).
  • the obtained mixture was stirred for 3 h, washed with saturated NaHCO 3 solution and saturated salt solution; dried over MgSO 4 , evaporated to dryness at reduced pressure; it gave 3.38 g of compound 6 (10), yield is nearly quantitative.
  • 4-Hydroxyquinoline 8(4) was prepared from aniline 8(1) according to the method described in J. Org. Chem. 2000, 23, 8005 , 3-bromo-4-hydroxyquinoline 8(5) - according to the procedure given in J. Am. Chem. Soc. 1946, 1229-1231 .
  • Methyl-(2-furan-2-yl-4-phenylsulfonyl-oxazol-5-yl)]-amines and methyl-(2-thiophen-2-yl-4-phenylsulfonyl-oxazol-5-yl)-amines were synthesized in analogous manner, provided that, N-(1,2,2,2-tetrachloroethyl)furan-2-carboxamide and N-(1,2,2,2-tetrachloroethyl)thiophene-2-carboxamide were used as 9(1)-amide, respectively.
  • Table 2 presents data concerning antagonistic activity K i for some compounds of the general formula 1 towards serotonin 5-HT 6 receptors in the setting of functional assay.
  • Table 2 Antagonist activity K i of compounds of the general formula 1 towards serotonin 5-HT 6 receptors in the setting of functional assay.
  • compositions for intramuscular, intraperitoneal or hypodermic injections Preparation of pharmaceutical composition in the form of compositions for intramuscular, intraperitoneal or hypodermic injections.
  • Compound 1.5(1) 500 mg
  • injectable water 100 ml
  • the resultant solution was filtered and placed into 1 ml ampoules, which were sealed and sterilized in an autoclave.
  • Nootropic action (enhancement of memory disturbed by Scopolamine) of compounds of the general formula 1 in the test "Passive Avoidance of mice in the Shuttle Chamber”.
  • a shuttle chamber Ugo Basile, Italy
  • the walls of one section were opaque, while the other section had a transparent cover.
  • the sections were connected through a hole which could be overlapped by vertical door.
  • the floor of the dark section was made of transverse metal bars on which DC current impulses could be fed. Experiments were carried out in aged male mice of BALB/c line weighing 20-25 grams.
  • mice On the first day of the experiment 30 minutes before training mice were injected intraperitoneally with physiological solution, Scopolamine (0.3 mg/kg), or Scopolamine in combination with compound 1.5(1). Each group consisted of 8 animals at least. The animals were placed in the light section, and latent period of the first entry into the dark chamber was registered. Then the vertical door was closed and the animal was punished by 0.6 mA DC current for 3 seconds. After that the animal was taken back to its home cage. In 22-24 hours the same animal was placed again in the light section of the shuttle chamber and latent period of its first entry into the dark section, the total time of its stay in the light section and the number of entries into dark section were registered. Each monitoring lasted for 5 minutes.
  • Scopolamine causes memory disturbance which was expressed in the form of decreasing of latent period of the first entry into dark section, decreasing the total time of stay in light section and increasing the number of entries into dark section
  • Nootropic action (enhancement of memory disturbed by MK-801) of compounds of the general formula 1.
  • Experiment was carried out, as in example 20. On the first day of the experiment 30 min before training mice were injected intraperitoneally with physiological solution of MK-801 (0.1 mg/kg). In parallel, independent groups of mice were injected intraperitoneally with physiological solution of MK-801 in combination with compound 1.5(1) before training. The experiment as described above was also conducted for compounds 1.1(9) and 1.8(7). The results obtained ( Fig 4-6 ) testify the property of compounds 1.1(9), 1.5(1) and 1.8(7) to produce nootropic action.
  • index of opened arms preference was calculated as ratio of the number of entries into opened arms as well as the time spent by animal in opened arms to the whole number of entries to arms of both types or, respectively, to the total time spent in opened and closed arms. Being in normal state animals avoid opened arms (index of preference makes 0.2-0.3). Compounds with anxiolytic activity (tranquilizing activity) run this value up to 0.5-0.6 and more, and also decrease the number of defecations without changing overall physical activity (general number of arm entries).
  • the test instrument consisted of a chamber made of transparent plexiglass (manufacturer - Columbia Instruments Company, USA) and placed on a platform; the latter was lodged inside the sound insulating chamber. High frequency sound column transmitting acoustic stimulus was located 2 cm away from the platform. Startle of animal resulted in vibrations of platform, which were detected by analog converter and registered by computer. Level of background noise made up 65 dB. Each animal received 4 stimuli of single testing (pulse) stimulus of 50 ms duration and 105 dB or prepulsory stimulus (pre-pulse) of 20 ms duration and 85 dB, after which in 30 ms pulse stimulus of 50 ms duration and 105 dB followed.
  • pulse single testing
  • pre-pulse prepulsory stimulus
  • Administration of Apomorphine which is used in experiments on animals for modelling of psychoto-like conditions, caused reduction of prepulse inhibition of startle, which reflected the lowering of CNS ability to filter sensory stimulus. The experiment was also carried out using compounds 1.1(9) and 1.8(7).
  • the test apparatus represented a plastic vessel filled with water up to height of 18 cm at 20-22°C. Experiments were carried out in aged male mice of BALB/c line weighing 20-24 grams. An animal was placed in water and for 15 minutes the duration of immobile hanging in water - so named behavioural despaire which is considered to be a measure of depressively-like state, was registered. The last 5 minutes of the test were used for estimation. Automated computerized detection of motion with video system and Any-maze program were used in test. The ability of compounds 1.1(9), 1.5(1 ) and 1.8(7) after 4 days administration of them in doses of 1 mg/kg to diminish the given parameter ( Fig 12 ) is regarded as evidence of their antidepressant action.
  • Antidepressant action of compounds of the general formula 1 in tail suspension test Experiments were carried out in aged male mice of BALB/c line weighing 20-24 grams. In the test mice were suspended by tail with scotch tape on holder over horizontal surface at a height of about 40cm, and for 3 minutes the total duration of complete immobility episodes which is considered to be a measure of depressively-like state was registered. Automated computerized detection of motion with video system and Any-maze program were used in test. The ability of compounds 1.1(9), 1.5(1) and 1.8(7) after 4 days administration of them in doses of 0.1 mg/kg to diminish the duration of complete immobility of mice ( Fig 13 ) is regarded as evidence of their antidepressant action.
  • the invention could be used in medicine, veterinary, biochemistry.

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